title: Alteration of 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor by ethanol in rat liver and mouse hepatoma cells.
abstract: Alcohol is a potential risk factor of type 2 diabetes, but its underlying mechanism is unclear. To explore this issue, Wistar rats and mouse hepatoma cells (Hepa 1-6) were exposed to ethanol, 8 g·kg(-1) ·d(-1) for 3 months and 100 mM for 48 h, respectively. Glucose and insulin tolerance tests in vivo were performed, and protein levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and glucocorticoid receptor (GR) in liver and Hepa 1-6 cells were measured. Alterations of key enzymes of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase), as well as glycogen synthase kinase 3a (GSK3 α ), were also examined. The results revealed that glucose levels were increased, and insulin sensitivity was impaired accompanied with liver injury in rats exposed to ethanol compared with controls. The 11β-HSD1, GR, PEPCK, G6Pase, and GSK3 α proteins were increased in the liver of rats treated with ethanol compared with controls. Ethanol-exposed Hepa 1-6 cells also showed higher expression of 11β-HSD1, GR, PEPCK, G6Pase, and GSK3 α proteins than control cells. After treatment of Hepa 1-6 cells exposed to ethanol with the GR inhibitor RU486, the expression of 11β-HSD1 and GR was significantly decreased. At the same time the increases in PEPCK, G6Pase, and GSK3 α levels induced by ethanol in Hepa 1-6 cells were also attenuated by RU486. The results indicate that ethanol causes glucose intolerance by increasing hepatic expression of 11β-HSD1 and GR, which leads to increased expression of gluconeogenic and glycogenolytic enzymes.
authors.affiliation: Department of Pharmacology, School of Norman Bethune Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Meng
authors.forename: Xueying
authors.initials: X
authors.lastname: Bao
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wei
authors.forename: Wenguang
authors.initials: W
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: B L Grégoire
authors.initials: BL
authors.lastname: Nyomba
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D000431:Ethanol / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D011965:Receptors, Glucocorticoid; D000431:Ethanol; D042842:11-beta-Hydroxysteroid Dehydrogenases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP)